Diaminedithiol derivatives and radiorhenium or radiotechnetium complex thereof; a liver cancer-treating composition comprising the radiorhenium complex and lipiodol; and a kit for preparation of the liver cancer-treating composition

ABSTRACT

The present invention relates to a novel diaminedithiol derivative or a pharmaceutically acceptable salt thereof; radiorhenium or radiotechneticum complex thereof; a composition for treating liver cancer comprising the radiorhenium complex and lipiodol; and, a preparative kit of the composition for treating liver cancer.  
     In the composition according to the invention, the diaminedithiol derivative is a novel compound in which long chain alkyl groups were introduced to diaminedithiol, capable of forming a radiorhenium or radiotechnetium complex thereof with an ease and leading to stronger van der Waals bonds with lipiodol. As a result, the complex becomes more stable in a medium, lipiodol, whereby the composition of the invention exhibits a high accumulation rate in liver cancer tissue when injected via hepatic artery, thereby capable of achieving an efficient treatment of liver cancer.

TECHNICAL FIELD

[0001] The present invention relates to a novel diaminedithiolderivative or a pharmaceutically acceptable salt thereof; a radiorheniumor radiotechnetium complex thereof; a composition for treating livercancer comprising the radiorhenium complex and lipiodol; and apreparative kit of the composition for treating liver cancer.

BACKGROUND ART

[0002] Liver cancer especially affects oriental countries, includingKorea at a high incidence and mortality rate. The liver cancer can betreated by surgical operation in an early stage, when metastasis ofcancer cells has not occurred and their size is small. However, as thedisease is progressed, the treatment by the surgical operation becomesineffective. In this case, hepatic arterial embolization is generallyused.

[0003] Normal liver tissue is supplied with blood and oxygen throughboth portal veins and arteries, particularly, for the blood the portalveins and arteries being responsible for 75% and 25%, respectively, ofthe total supply, and for the oxygen the portal veins and arteries beingresponsible for 50% and 50%, respectively, of the total supply. However,as for a cancerous tissue of the liver, the portal veins take 90% insupplying blood. Based on this fact, if embolic material embolizing tocapillary vessel is injected to the hepatic artery of a liver cancerpatient, the material is migrated mainly to the liver cancer tissue,causing embolization thereto. One example of the embolic materials islipiodol.

[0004] Lipiodol is a lipid-soluble contrast medium obtained byiodination and esterification of poppy seed oil. Lipiodol has beenemployed as a contrast medium for imaging lymph nodes. It is easily ableto cause capillary embolism due to 38 weight % iodine and high viscosityat room temperature. Therefore, injection of lipiodol to the hepaticartery of a patient with liver cancer results in lipiodol beingconcentrated into the liver cancer tissue. Using, such information,there were several attempts to treat liver cancer by injectinganticancer agent-assembled lipiodol to the liver cancer tissue.

[0005] A method by which lipiodol is labeled with a radioisotope andadministered via a hepatic artery to treat liver cancer had been used.It was reported that when administered to patients with liver cancer,¹³¹I-labelled lipiodol is accumulated in liver cancer tissue (M. Nakajoet al., Biodistribution and in vivo kinetics of iodine-131 lipiodolinfused via the hepatic artery of patients with hepatic cancer, J. Nucl.Med., 29: 1066-1077, 1988). And, distribution in vivo of ⁹⁰Y-labelledlipiodol was studied (S-J Wang et al., Preparation and biodistributionof yttrium-90 lipiodol in rats following hepatic arterial injection,Eur. J. Necl. Med., 22: 233-236, 1995). However, there are disadvantagesin that I-131 is an isotope not suitable for the treatment, and Y-90 iscostly and hard to be imaged, limiting the use thereof. Articles werepublished to report Re-188 labeling to overcome the above disadvantages(S-J Wang et al., Radiolabelling of lipiodol with generator-produced¹⁸⁸Re for hepatic tumor therapy, Appl. Radiat. Isot., 47: 267-271.,1996; S-J Wang et al., Biodistribution of rhenium-188 lipiodol infusedvia the hepatic artery of rats with hepatic tumors, Eur. J. Nucl. Med.,23:13-17, 1996). However, the methods presented by these articles needimprovement since the labeling method is complicated and the labelingefficiency and its stability are low.

[0006] To improve the labeling method, diaminedithiol derivatives withalkyl chain have been developed (T W Jackson et al., Rhenium diaminodithiol complexes. III Lipophilic ligands for endotherapeuticradiopharmaceuticals. Aust. J. Chem. 53:983-987). They synthesizeddiaminedithiol derivatives with long alkyl chain of C₁-C₁₄ and labeledthem with radiorhenium. What they found was that only diaminedithiolderivatives with alkyl chain of C₁-C₁₀ showed enough stability fortreatment of liver cancer. They found that diaminedithiol derivativeswith alkyl chain longer than C₁₀ were not stable. Actually, theyreported that the yield of complexing rhenium and diaminedithiolcontaining C₁₀ alkyl chain was so poor that they failed to get enoughamount of complex for analysis. It would have been even more difficultfor them to obtain rhenium complex with diaminedithiol containing longeralkyl chain in their experiment. That is why they gave up diaminedithiolcontaining alkyl chain longer than C₁₀. They claimed diaminedithiolderivatives with alkyl chain of C₁-C₁₀ for treatment of liver cancer inU.S. Pat. No. 5,496,533. However in our experiment, diaminedithiolcontaining alkyl chain longer than C₁₀ could make stable lipophiliccomplex with ¹⁸³Re. Furthermore, we found that diaminedithiolderivatives with alkyl chain shorter than C₁₃, which includes thecompounds in U.S. Pat. No. 5,496.533, were not lipophilic enough to beretained in the tissue, which would result in rapid clearance fromcancer tissue. We have proved that diaminedithiol derivatives shouldhave alkyl chain longer than C₁₄, and that is our major claim in thispatent.

[0007] Meanwhile, diaminedithiol has a structure represented in Formula1 below. It was synthesized and known to make stable lipophilic complexwith technetium or rhenium (HF Kung, et al. Synthesis andbiodistribution of neutral lipid-soluble Tc-99m complexes that cross theblood-brain barrier. J. Nucl. Med. 25:326-332, 1984). Davison et aldescribed a variety of complexes of substituted anionic diaminedithiolwith Tc-99m as an agent for imaging kidney, which was published on Mar.27, 1985 in Europe Pat. Appln. No. 135,160.

[0008] wherein, R₁ to R₁₂ are independently hydrogen, alkyl having C₁ toC₃, or —COOR (in which R is —CH₃, —C₂H₅ or —C₃H₇); provided that amongsubstituents R₁ to R₁₂, only R₃, R₅, and R₇ to R₁₀ may be —COOR.

[0009] A kit comprising a neutral lipid-soluble ester-substituted isdiaminedithiol is disclosed in Korean Pat. Laid-open No. 92-2107.According to the reference, using a method by which thiazolidine isdimerized via reduction to prepare a N,N′-1,2-ethylenebis-L-cysteinederivative and ester, thereof (Blondeau et al., Can. J. chem., 45:46,1967). ligand is synthesized and labeled with Tc-99m to form a neutrallipid-soluble complex, being directed to imaging blood flow in thebrain.

[0010] In U.S. Pat. No. 5,980.860 published on Nov. 9 1999, it isdescribed that diaminedithiol derivatives are synthesized by introducingtropane group to use as a radiopharmaceuticals for imaging dopaminetransporter.

DISCLOSURE OF THE INVENTION

[0011] Therefore, the present invention has been made in view of theabove problems, and it is an object of the present invention to providea novel diaminedithiol derivative and pharmaceutically acceptable saltsthereof.

[0012] It is a further object of the present invention to provide acomplex of diaminedithiol derivative-radiorhenium or a complex ofdiaminedithiol derivative-radiotechnetium.

[0013] It is yet another object of the present invention to provide acomposition for treating liver cancer comprising a complex of noveldiaminedithiol derivative-radiorhenium, which is able to be preparedeasily and is stable after preparation, characterized by its high anddurable accumulation in liver cancer tissue, thereby being capable ofefficiently treating liver cancer without any side effect.

[0014] In particular, it is an important object of the invention toprovide a more effective composition for treating liver cancer, whichcompensates for a shortcoming that a complex of diaminedithiol-rheniumfails to be retained in a tissue for a long time.

BEST MODE FOR CARRYING OUT THE INVENTION

[0015] The present invention relates to a novel diaminedithiolderivative having long chain alkyl groups, represented in Formula 2below (hereinafter, referred to as diaminedithiol derivative) or apharmaceutically acceptable salt thereof; a radiorhenium orradiotechnetium complex thereof; a composition for treating liver cancercomprising the radiorhenium complex and lipiodol; and, a preparative kitof the composition for treating liver cancer.

[0016] The diaminedithiol derivative of the present invention,represented in Formula 2 below, and pharmaceutically acceptable saltsthereof are novel compounds and form complexes with radiorhenium orradiotechnetium. The complex compound of diaminedithiolderivative-radiorhenium creates stronger Van der Waals bonds by theintroduction of lone chain alkyl groups. As a result, the complexbecomes more stable in the medium, lipiodol. Moreover, a technetiumcomplex of diaminedithiol derivative may be an agent for imaging bloodflow in the lung via intravenous injection after being dissolved inlipiodol or oil which is a liquid at room temperature.

[0017] wherein:

[0018] R₂, R₃, R₈ to R₁₄ are independently hydrogen or lower alkylhaving C₁ to C₅; R₄ and R₅ are independently hydrogen or lower alkylhaving C₁ to C₅ or they form oxo (═O) group; R₆ and R₇ are independentlyhydrogen or lower alkyl having C₁ to C₅ or they form oxo (═O) group, inwhich at least one of R₂ to R₁₄ is higher alkyl having C₁₅ to C₂₄ and R₄to R₇ don't form two oxo (═O) groups at the same time:

[0019] R₁ and R₁₅ are independently hydrogen or thiol protecting groupsuch as benzoyl, acetamidomethyl, diphenylmethyl, ethylaminocarbonyl,t-butyl, trityl and acetyl, or R₁ and R₁₅ together form a S—S bond; and,

[0020] n, o. p are independently 1 or 2.

[0021] In the above, if R₁ and R₁₅ are thiol protective groups, theyshould be removed immediately before or when being labelled to form athiol group.

[0022] In he above Formula 2, as for the preparation of a compositionfor treating liver cancer, diaminedithiol derivatives in which R₁₀ ishigher alkyl having C₁₅ to C₂₄, or pharmaceutically acceptable saltshereof are preferable. More preferably, diaminedithiol derivatives inwhich R₁₀ is higher alkyl having C₁₅ to C₂₀, or pharmaceuticallyacceptable salts thereof may be employed. In addition, it may beexpected that a diaminedithiol derivative in which R₁₀ is linear alkylwithout a branch, or pharmaceutically acceptable salts thereof offersmore desirable effects.

[0023] In the above Formula 2, diaminedithiol derivatives in which n, oand p are all together 1 or pharmaceutically acceptable salts thereofmay be preferably employed for the preparation of a composition fortreating liver cancer.

[0024] Furthermore, diaminedithiol derivatives in which all the aboveconditions are met; R₂, R₃, R₁₃ and R₁₄ are all together methyl; R₁, R₄,R₅, R⁶, R₇, R₈, R₉, R,₁₁, R₁₂ and R₁₅ are all together hydrogen, orpharmaceutically acceptable salts thereof may be most preferablyemployed.

[0025] Meanwhile, in the above Formula 2, R₄ and R₅ or R₆ and R₇, can beindependently oxo (═O) group. If the compound has two or more oxo (═O)groups, its suitability decreases as an ingredient for a composition fortreating liver cancer. Therefore, the compound which has only one oxo(═O) group may be preferably employed for the preparation of acomposition for treating liver cancer.

[0026] A composition for treating liver cancer of the inventioncomprises a complex of diaminedithiol derivative-radiorhenium andlipiodol. A method for preparing the composition comprises the steps ofreacting a diaminedithiol derivative, a reducing agent and an additivewith radiorhenium or radiotechnetium to form a complex and dissolvingthe complex in lipiodol.

[0027] Radiorhenium used herein for forming a complex with adiaminedithiol derivative is either ¹⁸⁶Re or ¹⁸⁸Re and radiotechnetiumused is ^(99m)Tc. A reducing agent is used to reduce radiorhenium orradiotechnetium so as to allow binding with diaminedithiol. The reducingagent may be, for example, tin chloride, vitamin C, iron chloride,dithionite or sodium sulfite, and especially, tin chloride ispreferable. Additives may be added for preventing the formation ofbyproducts upon radioisotope labeling and increasing the labelingefficiency as well as for improving a quality including chemical andphysical stabilities of the labeling. The additives may be, for example,tartaric acid, gluconic acid, glucoheptonic acid, lactic acid, MDP,lactose, EDTA, gentisic acid, and especially, tartaric acid ispreferable.

[0028] In view of the course of labeling with radiorhenium orradiotechnetium, when materials and methods disclosed in the prior art(S-J Wang et al., Radiolabelling of lipiodol with generator-produced¹⁸⁸Re for hepatic tumor therapy, Appl. Radiat. Isot., 47: 267-271, 1996)are employed for labeling, ammonium carbonate solution is boiled, aceticacid is added, followed by evaporation under a nitrogen gas atmosphere,taking over 5 hours to get through the serial steps. On the other hand,labeling the diaminedithiol derivative used in this invention withradiorhenium is achieved within 1 hour and the complex formed has anexcellent stability.

[0029] Lipiodol as a component for the composition of the invention, asdescribed in the above section, is a lipid-soluble material. It wasfound by Nakamura et al in 1983 that lipidol is selectively accumulatedin the liver cancer tissues. The composition according to the inventioncomprises lipiodol as a medium, being capable of accumulating a complexof diaminedithiol-radiorhenium or a complex ofdiaminedithiol-radiotechnetium, an active ingredient, in liver cancertissues or lung tissues. The lipiodol content in the composition is anyamount which can dissolve a complex of diaminedithiol-radiorheniumformed. Preferably, lipiodol may be employed in amount of 0.5 ml to 50ml, relative to 1 mg of a diaminedithiol derivative.

[0030] As an active ingredient of the invention, a complex ofdiaminedithiol-radiorhenium is so highly lipid-soluble that it is welldissolved in lipiodol, an oil-based X-ray contrast medium. Thus, whenlipiodol is used as a medium, injection of the complex ofdiaminedithiol-radiorhenium together with lipiodol through the hepaticartery causes embolization in capillary vessels of the liver cancertissue, thereby the active ingredient being accumulated. A complex ofdiaminedithiol-radiorhenium is highly lipid-soluble so it remainsdissolved in lipiodol and does not diffuse into surrounding tissues,whereby the complex is retained in the cancer tissue as long as lipiodolis held, finally achieving a selective radiation effect, thereby capableof selectively removing tumor cells.

[0031] With regard to the concrete method of preparing a composition fortreating liver cancer of the invention, first, a diaminedithiolderivative reacts with radiorhenium in the presence of a reducing agentand an additive to form a complex. To the complex in aqueous solution isadded lipiodol and the solution is mixed well. The lipid-soluble complexis mixed with lipiodol and the mixture is centrifuged, separating intotwo phases. The lower phase comprising lipiodol is taken out using asyringe to obtain a composition for treating liver cancer according tothe invention.

[0032] Another embodiment of the invention is a preparative kit of theabove composition for treating liver cancer comprising a first containercontaining a lyophilized diaminedithiol derivative, a reducing agent andan additive; and a second container containing lipiodol which can besubjected to a direct centrifugation. The reducing agent and additiveare defined as above. Meanwhile, radiorhenium may be supplied from othersources immediately before use.

[0033] Further, in the above preparative kit of the composition fortreating liver cancer, lipiodol may be supplied from other sources,thus, the kit is characterized by comprising a first containercontaining a lyophilized diaminedithiol derivative, a reducing agent andan additive, whereby a preparative kit comprising a complex ofdiaminedithiol derivative-radiorhenium in the composition for treatingliver cancer is also available.

[0034] Hereinafter, the present invention will be described in detail,in conjunction with various examples. These examples are provided onlyfor illustrative purposes, and the present invention is not to beconstrued as being limited to those examples.

EXAMPLE 1

[0035] Preparation of5-octyl-3,3,10,10-tetramethyl-1,2-dithia-5,8-diazacyclodecane (OTDD)

[0036] Partial Synthesis A: Preparation of3,3,10,10-tetramethyl-1,2-dithia-5,8-diazacyclodecane (TDD)

[0037] 29 g of 2-2′-dithio-bis(2-methylpropanal) was dissolved in asolution of 50 mg tosic acid in 280 ml benzene and added dropwise with12.6 g of 2-methyl-1,2-diaminopropane, while mixing well. The reactionmixture was refluxed for 2 hrs to remove water. Solvent was removedunder reduced pressure. The residue was dissolved in petroleum etherwith a low boiling point. Then, activated charcoal was added and themixture was then filtered. The filtrate was concentrated untilprecipitates began to be formed. The crystals were filtered, collectedand washed with cold petroleum ether to obtain light yellow crystals.The crystals thus obtained were dissolved in ethanol and added withsodium cyanoborohydride of the same equivalent while stirring gently.The solution was adjusted to pH 5.0 by adding glacial acetic acid. Thereaction was let to stand at room temperature for 2 hrs. Then, thereaction solution was heated to 60° C. and stirred for 6 hrs. At thistime, glacial acetic acid was added to maintain pH 5.0 until thereaction was completed. After 6 hrs, saturated ammonium chloridesolution (10 ml) was added, and the solution was stirred for anadditional 20 min. Solvent was removed under reduced pressure. Theresidue thereby obtained was added with 1 M sodium hydroxide solution (5ml) and dissolved. The resulting solution was extracted with chloroform(20 ml). The organic phase was washed with saturated sodium chloridesolution and dried over anhydrous sodium sulfate. After removing solventfrom this product under reduced pressure, a light brownish liquid wasobtained.

[0038] TLC (silica gel/diethylether:n-hexane:n-propylamine=7:3:1):R_(f=)0.3

[0039]¹H-NMR(CDCl₃): 1.24(s, 6H), 1.36(s, 6H), 2.34(s, 2H), 2.55˜2.59(d,2H, J=12.0 Hz), 2.80(s, 4H), 2.98˜3.02(d, 2H, J=12.0 Hz). MS(EI m/z)234.2(M+, 12%), 130.2(100%).

[0040] Partial Synthesis B: Preparation of OTDD

[0041] TDD (3.0 g, 12.8 mmol) prepared in the above section A wasdissolved in acetonitrile (30 ml) and stirred at room temperature for 1hr. To the solution was added 1-iodooctane (2.24 ml, 12.2 mmol) and thesolution was stirred at room temperature for 12 hrs. The reactionmixture was filtered and the filtrate was concentrated by distillingunder reduced pressure. The concentrate was separated by means of apreparative thin layer chromatography(diethylether:n-hexane:n-propylamine=30:30:1) to obtain a light yellowoil (1.11 g, 3.20 mmol, 26.3%).

[0042] TLC (silica gel/diethylether:n-hexane:n-propylamine=7:3:1):R_(f)0.7

[0043]¹H-NMR(CDCl₃): 0.88(t, 3H, J=6.8Hz), 1.21-1.38(m, 24H), 1.52(t,2H, J=7.1Hz), 1.83(bs, 1H), 2.47-2.86(m, 8H). MS(EI m/z) 346.4(M+, 17%),204.1(100%)

EXAMPLE 2

[0044] Preparation of5-dodecyl-3,3,10,10-tetramethyl-1,2-dithia-5,8-diazacyclodecane (DTDD)

[0045] TDD (3.0 g, 12.8 mmol) prepared in the above section A of Example1 was dissolved in acetonitrile (30 ml). Potassium carbonate (17.7 g,128 mmol) was added and the solution was stirred at room temperature for1 hr. To the solution was added 1-iododecane (3.06 ml, 12.2 mmol) andthe solution was stirred at room temperature for 12 hrs. The reactionmixture was filtered and the filtrate was concentrated by distillingunder reduced pressure. The concentrate was separated by means of apreparative thin layer chromatography(diethylether:n-hexane:n-propylamine=30:30:1) to obtain a light yellowoil (1.49 g, 3.70 mmol, 30.3%).

[0046] TLC (silica gel/diethylether:n-hexane:n-propylamine=7:3:1):R_(f)=0.7

[0047]¹H-NMR(CDCl₃): 0.88(t, 3H, J=6.8Hz), 1.22-1.35(m, 32H), 1.52(t,2H, J=7.1Hz), 1.96(bs, 1H), 2.55-2.87(m, 8H). MS(EI m/z) 402.4(M+, 14%),204.1(100%)

EXAMPLE 3

[0048] Preparation of5-hexadecyl-3,3,10,10-tetramethyl-1,2-dithia-5,8-diazacyclodecane (HTDD)

[0049] TDD (1.75 g, 7.47 mmol) prepared in the above A of Example 1 wasdissolved in acetonitrile (20 ml). Potassium carbonate (10.3 g, 74.7mmol) was added and the solution was stirred at room temperature for 1hr. To the solution was added 1-iodohexadecane (2.35 ml, 7.1 ml) and thesolution was stirred at room temperature for 12 hrs. The reactionmixture was filtered and the filtrate was concentrated by distillingunder reduced pressure. The concentrate was separated by means of apreparative thin layer chromatography(diethylether:n-hexane:n-propylamine=30:30:1) to obtain a light yellowoil (0.66 g, 1.40 mmol, 19.2%).

[0050] TLC (silica gel/diethylether:n-hexane:n-propylamine=7:3:1):R_(f)=0.7

[0051]¹H-NMR(CDCl₃): 0.88(t, 3H, J=6.8Hz), 1.23-1.35(m, 40H), 1.52(t,2H, J=7.1Hz), 2.05(bs, 1H), 2.55-2.86(m, 8H)

EXAMPLE 4

[0052] Preparation ofN1-(2-(tritylsulfanyl)ethyl)-2-hexadecyl-(2-(tritylsulfanyl)ethyl)amino)acetamide

[0053] Partial Synthesis A: Preparation of2-(tritylsulfanyl)-1-ethaneamine

[0054] 2-Aminoethanethiol hydrochloride (1.0 g, 8.6 mmol) was dissolvedin acetic trifluoride (10 ml) and added with triphenylmethanol (2.32 g,8.6 mmol). The resulting solution was stirred at room temperature for 1hr and concentrated by distilling under reduced pressure. The filtratewas diluted with ethyl acetate (50 ml) and washed with 3 M sodiumhydroxide aqueous solution, water, saturated sodium bicarbonate aqueoussolution, saturated sodium chloride aqueous solution in sequence. Theorganic phase was dried over anhydrous sodium sulfate and distilledunder reduced pressure to obtain a white solid of2-(tritylsulfanyl)-1-ethaneamine (2.32 g, 7.3 mmol, 85.2%).

[0055] mp: 142-143° C.

[0056] TLC (silica gel/ethyl acetate:n-hexane=1:1): R_(f)=0.1

[0057]¹H-NMR(CDCl₃): 2.33(t, 2H), 2.57(t, 2H). 4.76(bs, 2H), 7.21-7.31(m9H), 7.42-7.45(m, 6H)

[0058] Partial Synthesis B: Preparation ofN1-(2-(tritylsulfanyl)ethyl)-2-bromoacetamide

[0059] 2-(tritylsulfanyl)-1-ethaneamine (0.5 g, 1.6 mmol) was dissolvedin methylene chloride (10 ml) and added with triethylamine (0.22 ml, 1.6mmol). To the solution, bromoacetylbromide (0.14 ml, 1.6 mmol) inmethylene chloride (1 ml) was added dropwise. The resulting solution wasstirred at room temperature for 15 min and added with water (30 ml). Theorganic phase was washed with 1 M hydrogen chloride, water, saturatedsodium bicarbonate aqueous solution, and saturated sodium chlorideaqueous solution in sequence. The organic phase was dried over anhydroussodium sulfate and distilled under reduced pressure to obtain a whitesolid of N1-(2(tritylsulfanyl)ethyl)-2-bromoacetamide (0.67 g, 1.51mmol, 94.2%).

[0060] mp: 223-224° C.

[0061] TLC (silica gel/ethyl acetate:n-hexane=3:1): R_(f)=0.45

[0062]¹H-NMR(CDCl₃): 2.43(t, 2H), 3.11(q, 2H), 6.57(s, 1H), 7.21-7.31(m,9H), 7.42-7.45(m, 6H)

[0063] Partial Synthesis C: Preparation ofN1-(2-(tritylsulfanyl)ethyl)-2-((2(tritylsulfanyl)ethyl)amino)acetamideN1-(2-(tritylsulfanyl)ethyl)-2-bromoacetamide (0.5 g, 1.1 mmol) wasdissolved in methylene chloride (5 ml) and added with triethylamine(0.23 ml, 1.6 mmol). To the solution was added with2-(tritylsulfanyl)-1-ethaneamine (0.4 g, 1.1 mmol) and the resultingsolution was stirred at room temperature for 16 hrs. The organic phasewas dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure. The product was purified by means of columnchromatography to obtain a white solid ofN1-(2(tritylsulfanyl(ethyl)-2-((2-tritylsulfanyl)ethyl) amino)acetamide(0.4 g, 0.6 mmol, 55.3%).

[0064] mp: 88-92° C.

[0065] TLC (silica gel/ethyl acetate:n-hexane=2:1): R_(f)=0.4

[0066]¹H-NMR(CDCl₃): 2.37(q, 4H), 2.46(t, 2H), 3.04(s, 2H), 3.08(q, 2H),7.18-7.30(m, 18H), 7.39-7.44(m, 12H)

[0067] Partial Synthesis D: Preparation ofN1-(2-(tritylsulfanyl)ethyl)-2-(hexadecyl(2-(tritylsulfanyl)ethyl)amino)acetamide

[0068]N1-(2-(tritylsulfanyl)ethyl)-2-((2-(tritylsulfanyl)ethyl)amino)acetamide(0.1 g, 0.15 mmol) was dissolved in anhydrous acetonitrile (5 ml) andadded potassium carbonate (9243 mg, 1.5 mmol). The resulting solutionwas stirred at room temperature for 1 hr and added with 1-iodohexane (32μl, 0.097 ml) in chloroform (1.5 ml). The solution was stirred at 45° C.for 12 hrs. Solvent was removed under reduced pressure. After addingchloroform (10 ml), the solution was filtered and the filtrate wasconcentrated and purified by means of column chromatography to obtain ayellow solid ofN1-(2-(tritylsulfanyl)ethyl)-2-hexadecyl(2-(tritylsulfanyl)ethyl)amino)acetamide(44 mg, 32.5%).

[0069] mp: 188-193° C.

[0070] TLC (silica gel/ethyl acetate:n-hexane=2:1): R_(f)=0.8

[0071]¹H-NMR(CDCl₃): 0.88(t, 2H), 1.23-1.35(m, 30H), 2.37(q, 4H),2.46(t, 2H), 3.04(s, 2H), 3.08(q, 2H), 7.18-7.30(m, 18H), 7.39-7.44(m,12H)

EXAMPLE 5

[0072] Preparation of ¹⁸⁸Re-OTDD

[0073] OTDD (0.5 mg, 1.45 μmol) and glucoheptonic acid (200 mg, 960μmol) were mixed with 0.1 M hydrogen chloride solution (0.125 ml) andadded with stannous chloride dihydrate (10 mg, 44 μmol) in 0.0132 Mhydrogen chloride aqueous solution (1 ml). To the mixed solution wasadded ¹⁸⁸Re-perrhenic acid solution (20 mCi, 2.5 ml) and the resultingsolution was incubated in a water bath at 100° C. for 1 hr. The productwas obtained at 41.5% yield.

[0074] ITLC-SG (ethyl acetate): R_(f)=0.9

EXAMPLE 6

[0075] Preparation of ¹⁸⁸Re-DTDD

[0076] DTDD (0.5.mg, 1.24 μmol) was dissolved in ethanol (0.1 ml) andadded with stannum powder (5 mg, 42 μmol) dissolved in 10.2 M HClaqueous solution (50 μl). To the mixed solution was added a solution (1ml) of glucoheptonic acid (200 mg, 960 μmol) and then, ¹⁸⁸Re-perrhenicacid aqueous solution (20 mCi, 3 ml) was added. The resulting solutionwas incubated in a water bath at 100° C. for 1 hr. The product wasobtained at 23.3% yield.

[0077] ITLC-SG (ethyl acetate): R_(f)=0.9

EXAMPLE 7

[0078] Preparation of ¹⁸⁸Re-HTDD

[0079] HTDD (0.5 mg, 1.09 μmol) was dissolved in ethanol (0.1 ml) andadded with stannum powder (5 mg, 42 μmol) dissolved in 10.2 M HClaqueous solution (50 μl). To the mixed solution was added an aqueoussolution (1 ml) of glucoheptonic acid (200 mg, 960 μmol) and then, added¹⁸⁸Re-perrhenic acid aqueous solution (20 mCi, 3 ml). The resultingsolution was incubated in a water bath at 100° C. for 1 hr. The productwas obtained at 14.3% yield.

[0080] ITLC-SG (ethyl acetate): R_(f)=0.9

EXAMPLE 8

[0081] Preparation of ¹⁸⁸Re-Labelled Compound in Lipiodol Solution

[0082] To the ¹⁸⁸Re-labelled reaction mixture prepared in the foregoingExamples 4 to 6, lipiodol (5 ml) was added, mixed well and the solutionwas centrifuged at 3000 rpm for 10 min. The supernatant was removed and2 ml saline was added. After mixing well, the resulting solution wascentrifuged again at 3000 rpm for 10 min and the supernatant was removedto recover a lower phase of lipiodol.

EXPERIMENTAL EXAMPLE 1

[0083] Observation of Increased Accumulation and Retention of¹⁸⁸Re-Labelled Compounds in Animal Tissues

[0084] Mice (ICR) were administered with an injection of ¹⁸⁸Re-labelledcompound in lipiodol solution which was prepared in the Example 7 viathe tail vein. Radioactivity distributed in tissues and weight of eachtissue were measured to calculate the percentage of radioactivity pergram of unit tissue relative to total radioactivity administered.

[0085] As radiation accumulation mechanism in the lung and the livercancer are similar, it is convenient to detect the level of radiationaccumulating in the lung of a mouse suffering from liver cancer. Asfound in Tables 1 to 4, compounds with a long side chain (Tables 2 to 4)more readily accumulated in the lung, and the clearance rate is slowerthan for compounds without a long side chain (Table 1). Therefore, itcan be inferred that a radiorhenium complex of a diaminedithiolderivative having a long side chain is effective for treating livercancer. TABLE 1 Biodistribution of the solution of ¹⁸⁸Re-TDD in lipiodolin mice Time post-injection 10 min. 1 hr 24 hr Specimen 4 mice 4 mice 3mice Blood 4.4 ± 0.4 3.0 ± 0.7 0.6 ± 0.1 Muscle 4.1 ± 0.9 0.9 ± 0.3 0.2± 0.2 Fat 6.4 ± 0.6 2.5 ± 0.2 0.2 ± 0.0 Heart 9.8 ± 0.7 1.9 ± 0.2 0.5 ±0.1 Lung 84.3 ± 25.8 15.7 ± 4.6  3.1 ± 0.2 Liver 25.2 ± 4.1  22.9 ± 3.8 3.6 ± 0.7 Spleen 3.5 ± 0.5 1.7 ± 0.2 0.4 ± 0.1 Stomach 3.6 ± 0.6 10.7 ±1.3  3.2 ± 2.3 Small intestine 6.9 ± 1.6 22.3 ± 4.6  25.7 ± 12.8 Kidney13.5 ± 2.5  6.2 ± 2.5 0.8 ± 0.1

[0086] TABLE 2 Biodistribution of the solution of ¹⁸⁸Re-OTDD in lipiodolin mice Time post- Injection 10 min 30 min 1 hr 3 hr 24 hr Specimen 3mice 3 mice 4 mice 3 mice 3 mice Blood 5.2 ± 1.8 3.8 ± 0.4 3.1 ± 0.5 2.8± 0.3 0.6 ± 0.0 Muscle 1.5 ± 0.2 1.2 ± 0.2 0.9 ± 0.2 0.5 ± 0.1 0.2 ± 0.0Fat 3.6 ± 0.7 2.2 ± 0.2 1.6 ± 0.4 1.3 ± 0.4 0.4 ± 0.1 Heart 6.3 ± 1.74.4 ± 0.3 2.7 ± 1.0 1.9 ± 0.4 0.7 ± 0.1 Lung 138.4 ± 19.8  97.4 ± 20.787.0 ± 13.2 61.6 ± 10.0 22.8 ± 3.3  Liver 15.1 ± 2.4  21.6 ± 4.9  20.1 ±3.3  19.7 ± 6.7  7.3 ± 1.5 Spleen 2.6 ± 0.3 2.3 ± 0.1 1.9 ± 0.6 1.8 ±0.3 2.0 ± 2.0 Stomach 3.5 ± 1.3 12.9 ± 6.6  11.1 ± 3.1  15.5 ± 6.6  3.6± 1.8 Small intestine 3.6 ± 0.3 8.0 ± 2.0 13.0 ± 3.7  23.4 ± 0.3  19.8 ±12.0 Kidney 8.0 ± 1.2 6.6 ± 0.3 5.6 ± 0.9 4.0 ± 0.5 1.5 ± 0.4

[0087] TABLE 3 Biodistribution of the solution of ¹⁸⁸Re-DTDD in lipiodolin mice Time post- Injection 10 min 30 min 1 hr 3 hr 24 hr Specimen 3mice 3 mice 4 mice 4 mice 3 mice Blood 13.0 ± 0.6  9.5 ± 1.1 7.0 ± 0.85.1 ± 1.2 0.6 ± 0.2 Muscle 2.4 ± 0.1 2.0 ± 0.2 1.5 ± 0.3 1.0 ± 0.2 0.3 ±0.0 Fat 5.5 ± 0.4 4.4 ± 0.8 4.1 ± 0.6 2.4 ± 0.4 0.6 ± 0.2 Heart 9.1 ±2.3 5.0 ± 0.9 5.5 ± 0.4 2.7 ± 0.7 1.5 ± 0.3 Lung 137.4 ± 13.1  85.1 ±7.1  82.2 ± 15.1 61.9 ± 10.3 47.2 ± 9.2  Liver 14.9 ± 0.7  14.6 ± 2.2 13.2 ± 2.8  7.7 ± 0.6 3.3 ± 1.1 Spleen 5.6 ± 0.3 4.8 ± 0.4 3.5 ± 0.5 2.9± 0.6 3.3 ± 1.0 Stomach 18.3 ± 4.4  36.0 ± 5.9  49.2 ± 7.0  37.7 ± 12.35.4 ± 1.6 Small intestine 4.8 ± 0.3 8.3 ± 0.7 9.7 ± 1.2 11.6 ± 0.3  9.2± 6.9 Kidney 9.9 ± 0.7 7.4 ± 0.5 6.2 ± 0.7 5.2 ± 0.7 1.9 ± 0.3

[0088] TABLE 4 Biodistribution of the solution of ¹⁸⁸Re-HTDD in lipiodolin mice Time post- Injection 10 min 30 min 1 hr 3 hr 24 hr Specimen 4mice 4 mice 3 mice 4 mice 4 mice Blood 8.1 ± 1.5 9.1 ± 5.3 4.2 ± 0.5 2.8± 0.5 0.6 ± 0.1 Muscle 1.9 ± 0.3 1.5 ± 0.2 1.1 ± 0.2 0.8 ± 0.2 0.4 ± 0.1Fat 3.9 ± 1.5 2.8 ± 0.5 2.7 ± 0.6 2.0 ± 0.6 0.8 ± 0.3 Heart 9.4 ± 3.06.0 ± 1.1 4.7 ± 0.9 4.5 ± 0.8 2.2 ± 0.8 Lung 211.3 ± 30.0  185.6 ± 20.9 177.8 ± 18.4  157.3 ± 28.6  118.0 ± 19.5  Liver 11.6 ± 1.7  15.9 ± 1.6 14.4 ± 2.5  9.0 ± 1.8 5.6 ± 1.0 Spleen 3.6 ± 0.8 3.1 ± 0.2 3.0 ± 0.8 2.7± 0.1 9.3 ± 5.2 Stomach 7.4 ± 1.6 15.1 ± 2.9  21.0 ± 1.7  19.3 ± 4.0 5.5 ± 1.7 Small intestine 3.4 ± 0.5 6.5 ± 0.6 9.3 ± 1.0 12.2 ± 1.3  6.2± 3.4 Kidney 7.0 ± 1.8 6.5 ± 0.9 6.1 ± 1.4 6.2 ± 1.2 3.3 ± 0.7

Industrial Applicability

[0089] As apparent from the above description, the present inventionprovides novel diaminedithiol derivatives or pharmaceutically acceptablesalts thereof, and radiorhenium or radiotechnetium complex thereof. Thepresent invention also provides a composition for treating liver cancercomprising a complex of diaminedithiol derivative-radiorhenium, whichcan be prepared easily and is stable after preparation, characterized byits high rate of accumulation and retention in liver cancer tissue,thereby being capable of achieving an efficient treatment of livercancer without any side effects.

[0090] Although the preferred embodiments of the present invention havebeen disclosed for illustrative purposes, those skilled in the art willappreciate that various modifications, additions and substitutions arepossible, without departing from the scope and spirit of the inventionas disclosed in the accompanying claims.

What we claim is:
 1. A diaminedithiol derivative of Formula 2 or apharmaceutically acceptable salt thereof:

wherein: R₂, R₃, R₈ to R₁₄ are independently hydrogen or lower alkylhaving C₁ to C₅; R4 and R₅ are independently hydrogen or lower alkylhaving C₁ to C₅ or they form oxo (═O) group; R6 and R₇ are independentlyhydrogen or lower alkyl having C₁ to C₅ or they form oxo (═O) group, inwhich at least one of R₂ to R₁₄ is higher alkyl having C₁₅ to C₂₄ and R₄to R₇ don't form two oxo (═O) groups at the same time; R₁ and R₁₅ areindependently hydrogen or thiol protecting group such as benzoyl,acetamidomethyl, diphenylmethyl, ethylaminocarbonyl, t-butyl, trityl andacetyl, or R₁ and R₁₅ together form a S—S bond; and, n, o, p areindependently 1 or
 2. 2. The diaminedithiol derivative or apharmaceutically acceptable salt thereof according to claim 1, whereinR₁₀ is higher alkyl having C₁₅ to C₂₄.
 3. The diaminedithiol derivativeor a pharmaceutically acceptable salt thereof according to claim 1,wherein R₁₀ is higher alkyl having C₁₅; to C₂₀.
 4. The diaminedithiolderivative or a pharmaceutically acceptable salt thereof according toclaim 2 or claim 3, wherein R₁₀ is linear alkyl without a branch.
 5. Thediaminedithiol derivative or a pharmaceutically acceptable salt thereofaccording to claim 4, wherein n, o and p are all together
 1. 6. Thediaminedithiol derivative or a pharmaceutically acceptable salts thereofaccording to claim 5, wherein R₂, R₃, R₁₃ and R₁₄ are all togethermethyl and R₁, R₄, R₅, R₆, R₇, R8, R₉, R₁₁, R₁₂ and R₁₅ are all togetherhydrogen.
 7. The diaminedithiol derivative or a pharmaceuticallyacceptable salts thereof according to claim 1, wherein R₄ and R₅ formoxo (═O) group.
 8. The diaminedithiol derivative or a pharmaceuticallyacceptable salts thereof according to claim 1, wherein R₆ and R₇ formoxo (═O) group.
 9. A complex of a diaminedithiol derivative according toany one of claim 1 to claim 8 with radiorhenium or radiotechnetium. 10.A composition for treating liver cancer comprising a complex of adiaminedithiol derivative according to any one of claim 1 to claim 8with radiorhenium, and lipiodol.
 11. A pharmaceutically acceptablenon-pyrogenic, sterile preparative kit of the composition for treatingliver cancer according to claim 10 comprising a first containercontaining a lyophilized diaminedithiol derivative according to any oneof claim 1 to claim 8, a reducing agent and additives; and a secondcontainer containing lipiodol.
 12. The pharmaceutically acceptablenon-pyrogenic, sterile preparative kit of the composition for treatingliver cancer according to claim 11, wherein the reducing agent and theadditive are tin chloride and tartaric acid, respectively.
 13. Apharmaceutically acceptable non-pyrogenic, sterile preparative kit of acomplex of diaminedithiol derivative-radiorhenium in the composition fortreating liver cancer according to claim 10 comprising a first containercontaining a lyophilized diaminedithiol derivative according to any oneof claim 1 to claim 8, a reducing agent and an additive.
 14. Thepharmaceutically acceptable non-pyrogenic, sterile preparative kit of acomplex of diaminedithiol derivative-radiorhenium according to claim 13,wherein the reducing agent and the additive are tin chloride andtartaric acid, respectively.